Recent cellular analyses of the aging brain have revealed that phenotypic shifts in markers of neurotransmission are likely to be prime contributors to functional decline such as age-related memory impairment. Such studies have successfully dissociated this important set of age-related processes from the neuron loss and degenerative events associated with Alzheimer's Disease (AD). From this perspective, the health of the excitatory circuit and the glutamatergic synapse has become a focal point for aging research. In addition, there is increasing evidence for extensive plasticity at the synapse involving specific receptor subunits and associated proteins that may profoundly impact function. We will apply these concepts of phenotype plasticity to the neurobiology of aging, and test the hypothesis that aging results in shifts in glutamate receptors (GluRs) in a subset of hippocampal and neocortical circuits that could result in age-related memory impairment. This will involve the application of high resolution, quantitative analyses of the morphologic and molecular attributes of the glutamatergic synapse under a variety of conditions across four Specific Aims. Specific Aim 1 involves the analysis of age-related shifts in the GluR profile (e.g., multiple NMDA and AMPA receptor subunits) in key hippocampal circuits in young and aged rat and monkey cohorts that have been behaviorally characterized. The combined neurobiological/behavioral database allows for the direct linkage of the cellular and synaptic observations to age-related behavioral impairments. Specific Aim 2 will test the hypothesis that corticocortical connections between temporal and prefrontal association regions will display structural and neurochemical age-related alterations that could underlie age-related cognitive impairment. These studies will be carried out in Macaque monkeys, where we will characterize phenotypic changes in the aging corticocortical circuit, particularly with respect to the synaptic NMDA and AMPA receptors mediating inputs to these corticocortical neurons. Specific Aim ,3 will use a rat lesion model to investigate GluR plasticity in the context of individual and combined loss of two hippocampal inputs that are highly vulnerable in AD and aging; the perforant path input from entorhinal cortex, and the cholinergic input from the medial septal/diagonal band complex. Specific Aim 4 will delineate the cellular and synaptic adjustments in NMDA and AMPA receptors that occur in a transgenic mouse that overexpresses a single subunit, NR2B, which results in enhanced learning and memory. These Specific Aims converge on critical issues of GluR plasticity, synaptic specificity, and aging to delineate the phenotypic alterations of hippocampal and neocortical circuits that lead to impaired memory.